Dexamethasone enhances CTLA-4 expression during T cell activation
Dexamethasone enhances CTLA-4 expression during T cell activation
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DOI：
10.1007/s000180050403
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发表时间：
1999-09-01
影响因子：
8
通讯作者：
Feige, U
中科院分区：
文献类型：
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作者：
Xia, M;Gasser, J;Feige, U
抗原呈递细胞上的B7和T细胞上的CD 28的共刺激相互作用增强T细胞活化，导致T细胞长期增殖、分化和产生大量细胞因子，如白细胞介素（IL）-2。CTLA-4是一种共刺激受体，与CD 28具有31%的同源性，并以更高的亲和力结合B7家族成员。CTLA-4在T细胞活化后在细胞内和细胞表面瞬时表达。我们研究了CTLA-4表达的动力学和地塞米松对T细胞活化过程中CTLA-4表达的影响，在培养的小鼠脾细胞刺激的混合物的固定化抗-CD 3和抗-CD 28单克隆抗体（抗-CD 3/CD 28 mAb）或刀豆球蛋白A（ConA）。CTLA-4表达在第2天达到峰值，并在7天后恢复到背景水平。发现地塞米松以剂量依赖性方式增强CTLA-4表达，其EC 50有效浓度50%为约10（-8）M。相反，其他免疫抑制剂，如雷帕霉素或环孢菌素A对CTLA-4表达分别没有或有抑制作用。在抗CD 3/CD 28单抗诱导的小鼠脾T细胞活化过程中，地塞米松也刺激CD 28表达，但抑制IL-2 R表达。活化的小鼠T细胞的裂解物的Western印迹分析显示，在抗CD 3/CD 28 mAb诱导的活化期间，地塞米松使CTLA-4蛋白水平增加两倍。地塞米松也增加了CTLA-4信使RNA的两倍，定量的核糖核酸酶保护试验。地塞米松对CTLA-4表达的影响是糖皮质激素特异性的，并且被糖皮质激素受体拮抗剂米非司酮（RU 486）完全抑制，表明地塞米松对CTLA-4表达的影响是通过糖皮质激素受体介导的。总之，免疫抑制剂地塞米松实际上刺激CTLA-4的表达，这是参与下调T细胞活化。
T cell activation is enhanced by the costimulatory interaction of B7 on antigen-presenting cells and CD28 on T cells, resulting in long-term T cell proliferation, differentiation and production of large amounts of cytokines, such as interleukin (IL)-2. CTLA-4 is a co-stimulation receptor that shares 31% homology with CD28 and binds B7 family members with higher affinity. CTLA-4 is transiently expressed intracellularly and on the cell surface following activation of T cells. We have studied the kinetics of CTLA-4 expression and the effects of dexamethasone on CTLA-4 expression during T cell activation in cultures of mouse spleen cells stimulated by a mixture of immobilized anti-CD3 and anti-CD28 monoclonal antibodies (anti-CD3/CD28 mAb) or concanavalin A (ConA). CTLA-4 expression peaked on day 2 and returned to background levels after 7 days. Dexamethasone was found to potentiate CTLA-4 expression in a dose-dependent manner with an EC50 effective concentration 50%) of about 10(-8) M. In contrast, other immunosuppressive agents, such as rapamycin or cyclosporin A had no or an inhibitory effect on CTLA-4 expression, respectively. Dexamethasone also stimulated CD28 expression, but inhibited IL-2R expression during anti-CD3/CD28 mAb-induced mouse splenic T cell activation. Western blot analyses of lysates of activated mouse T cells showed that dexamethasone increased CTLA-4 protein levels twofold during anti-CD3/CD28 mAb-induced activation. Dexamethasone also enhanced CTLA-4 messenger RNA twofold as quantified by ribonuclease protection assay. The effects of dexamethasone on CTLA-4 expression were glucocorticoid-specific and completely inhibited by the glucocorticoid receptor antagonist mifepristone (RU486), indicating that the effect of dexamethasone on CTLA-4 expression is mediated through the glucocorticoid receptor. In conclusion, the immunosuppressive agent dexamethasone actually stimulates CTLA-4 expression, which is involved in downregulation of T cell activation.